Phosphorylation process plays an important role in the structural organization of neuronal cytoskeleton. Synthesis, transport and assembly of neurofilament (NF) proteins are developmentally and spatially regulated by specific kinases that extensively phosphorylate different motifs such as Lys-Ser-Pro (KSP) repeats in the carboxyl-terminal tail domain of NF- M and NF-H. This phosphorylation stabilizes the NF network in the axon, and to affect the axonal transport and conduction velocity in the neurons. Cyclin dependent kinase-5 (Cdk5) is believed to phosphorylate KSP motifs in NF and tau protein. The later phosphorylation occurs exclusively at the same sites found in the tau protein from Alzheimer's disease brain. Abnormal NF phosphorylation has also been associated with neuro-degenerative diseases. In order to delineate precise roles of specific kinases in neuro-degenerative process in vivo, we generated Cdk5 null mouse which exhibits abnormal corticogenesis associated with a lack of cortical laminar structure and cerebellar foliation; the large neurons in the brain stem and in the spinal cord showed chromatolytic changes with the accumulation of NF immunoreactivity. Subsequent analysis of Cdk5 null phenotype revealed abnormal migration of cortical neurons was associated with the normal reelin and mdab-1 expression indicating a new pathway through which Cdk5 exerts its effects on the neuronal migration and corticogenesis. Chimeras generated using Cdk5 null embryonic stem cells indicated cell-autonomous nature of Cdk5 effects on the neuronal migration.